The ability to produce images of the inside of a living organism without invasive surgery has been a major advancement in medicine over the last one hundred years. Imaging techniques such as X-ray computer tomography (CT) and magnetic resonance imaging (MRI) have given doctors and scientists the ability to view high-resolution images of anatomical structures inside the body. While this has led to advancements in disease diagnosis and treatment, a large set of diseases causes changes in anatomical structure only in the late stages of the disease or never at all. This has given rise to a branch of medical imaging that captures certain metabolic activities inside a living body. Positron emission tomography (PET) is in this class of medical imaging.
Positron Emission Tomography
PET is a medical imaging modality that takes advantage of radioactive decay to measure certain metabolic activities inside living organisms. PET imaging systems comprise three main components, indicated schematically in FIG. 1, a radioactive tracer that is administered to the subject to be scanned, a scanner that is operable to detect the location of radioactive tracer (indirectly as discussed below), and a tomographic imaging processing system.
The first step is to produce and administer a radioactive tracer 90, comprising a radioactive isotope and a metabolically active molecule. The tracer 90 is injected into the body to be scanned 91. After allowing time for the tracer 90 to concentrate in certain tissues, the body 91 is positioned inside the scanner 92. The radioactive decay event for tracers used in conventional PET studies is positron emission. Radioactive decay in the tracer 90 emits a positron e+. The positron e+ interacts with an electron e− in the body in an annihilation event that produces two 511 KeV anti-parallel photons or gamma photons γ. The scanner 92 detects at least some of the 511 KeV photons γ generated in the annihilation event.
The scanner 92 includes a ring of sensors and front-end electronics that process the signals generated by the sensors. The sensors typically comprise scintillator crystals or scintillators 93 and photomultiplier tubes (PMT), silicon photomultipliers (SiMP) or avalanche photo diodes (APD) 94. The scintillator 93 interacts with the 511 KeV gamma photons γ to produce many lower-energy photons, typically visible light photons. The PMT, SiMP, or APD 94 detects the visible light photons and generate a corresponding electrical pulse or signal. The electric pulses are processed by front-end electronics to determine the parameters or characteristics of the pulse (i.e., energy, timing). Unless the context implies otherwise, for convenience references to a PMT, SiMP or APD herein will be understood to include any mechanism or device for detecting gamma photons such as 511 KeV photons and producing lower-energy photons such as visible light photons in response.
Finally, the data is sent to a host computer 95 that performs tomographic image reconstruction to turn the data into a 3-D image.
Radiopharmaceutical
To synthesize the tracer 90, a short-lived radioactive isotope is attached to a metabolically active molecule. The short half-life reduces the subject's exposure to ionizing radiation, but generally requires the tracer 90 be produced close to the scanner. The most commonly used tracer is fluorine-18 flourodeoxyglucose ([F-18]FDG), an analog of glucose that has a half-life of 110 minutes. [F-18]FDG is similar enough to glucose that it is phosphorylated by cells that utilize glucose, but does not undergo glycolysis. Thus, the radioactive portion of the molecule becomes trapped in the tissue. Cells that consume a lot of glucose, such as cancers and brain cells, accumulate more [F-18]FDG over time relative to other tissues.
After sufficient time has passed for the tissue of interest to uptake enough tracer 90, the scanner 92 is used to detect the radioactive decay events, i.e., by detecting the 511 KeV photons. When a positron is emitted, it typically travels a few millimeters in tissue before it annihilates with an electron, producing two 511 KeV photons directed at 180°±23° from one another.
Photon Scintillation
Most of the 511 KeV photons will pass through the body tissue (and other materials) without significant interaction. While this typically allows the photon to travel through and exit the body, the gamma photons are difficult to detect. Photon detection is the task of the scintillator 93. A scintillator 93 absorbs gamma photons and emits lower energy photons, typically visible light photons. A scintillator 93 can be made from various materials including plastics, organic and inorganic crystals, and organic liquids. Each type of scintillator has a different density, index of refraction, timing characteristics, and wavelength of maximum emission.
In general, the density of the scintillator crystal determines how well the material stops the gamma photons. The index of refraction of the scintillator crystal and the wavelength of the emitted light affect how easily light can be collected from the crystal. The wavelength of the emitted light also needs to be matched with the device that will turn the light into an electrical pulse (e.g., the PMT) in order to optimize the efficiency. The scintillator timing characteristics determine how long it takes the visible light to reach its maximum output (rise time) and how long it takes to decay (decay time). The rise and decay times are important because the longer the sum of these two times, the lower the number of events a detector can handle in a given period, and thus the longer the scan will take to get the same number of counts. Also, the longer the timing characteristics, the greater the likelihood that two events will overlap (pile-up) and data will be lost.
The 511 KeV photons may undergo two types of interactions within the scintillator 93—Compton scattering, wherein the photon will lose energy and change direction, and photoelectric absorption. For example, a particular gamma photon may (i) experience photoelectric absorption in its first interaction in the scintillator crystal, (ii) undergo Compton scattering one or more times within the crystal prior to photoelectric absorption, or (iii) may undergo Compton scattering one or more times within the crystal before being ejected from the crystal.
Photomultiplier Tubes
Attached to the scintillator 93 are electronic devices that convert the visible light photons from the scintillator 93 into electronic pulses. The two most commonly used devices are PMTs and APDs. A PMT is a vacuum tube with a photocathode, several dynodes, and an anode that has high gains to allow very low levels of light to be detected. An APD is a semiconductor version of the PMT. Another technology that is currently being studied for use in PET scanners is SiPM. SiPMs comprise an array of semiconducting photodiodes that operate in Geiger mode so that when a photon interacts and generates a carrier, a short pulse of current is generated. In an exemplary SiPM, the array of photodiodes comprises about 103 diodes per mm2. All of the diodes are connected to a common silicon substrate so the output of the array is a sum of the output of all of the diodes. The output can therefore range from a minimum wherein one photodiode fires to a maximum wherein all of the photodiodes fire. This gives these devices a linear output even though they are made up of digital devices.
Image Reconstruction
An important advantage of PET imaging is that the annihilation event produces two substantially anti-parallel 511 KeV photons. Therefore, with detectors disposed around the body being imaged, two detection interactions may be observed at roughly the same time (coincident interactions) in two oppositely-disposed detector modules. (Throughout this document, detector modules, sensors, etc. that are disposed opposite each other means refers to distinct detector modules that are within each others field of view.) The annihilation event producing the 511 KeV photons will be located somewhere on the line connecting the two photon detection points. The line connecting two coincident interactions is referred to as the line of response (LOR). When enough coincident events have been detected, image reconstruction can begin. Essentially the detected events are separated into parallel lines of response (interpreted path of photon pair) that can be used to create a 3-D image using computer tomography. Methods for creating images using computer tomography are well known in the art. It will be appreciated that the accuracy of the 3-D PET images is dependent on the accuracy of the estimated LORs.
While PET, MRI, and CT are all common medical imaging techniques, the information obtained from the different modalities is quite different. MRI and CT give anatomical or structural information. That is, they produce a picture of the inside of the body. This is great for problems such as broken bones, torn ligaments or anything else that presents as abnormal structure. However, MRI and CT do not indicate metabolic activity. This is the domain of PET. The use of metabolically active tracers means that the images produced by PET provide functional or biochemical information.
Oncology (study of cancer) is currently the most common application of PET. Certain cancerous tissues metabolize more glucose than normal tissue. [F-18]FDG is close enough to glucose that cancerous cells readily absorb it and, therefore, they have high radioactive activity relative to background tissue during a scan. This enables a PET scan to detect some cancers before they are large enough to be seen on an MRI scan. PET scan information is also very useful for monitoring treatment progression as the quantity of tracer uptake can be tracked over the progression of the therapy. If a scan indicates lower activity in the same cancerous tissue after therapy, it indicates the therapy is working.
PET is also useful in neurology (study of the nervous system) and cardiology (study of the heart). An interesting application in neurology is the early diagnosis of Parkinson's disease. Tracers have been developed that concentrate in the cells in the brain that produce dopamine, a neurotransmitter. In patients with Parkinson's disease, neurons that produce dopamine reduce in number. Therefore, a scan of a Parkinson's patient would have less activity than a healthy patient's. This can lead to early diagnosis, since many of the other early signs of Parkinson's are similar to other diseases.
There remains a need for continued improvements in the cost, efficiency and accuracy of PET systems.